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XIAP discriminates between type I and type II FAS-induced apoptosis

机译:XIAP区分FAS诱导的I型和II型凋亡

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摘要

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic β-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein ) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and β-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
机译:FAS(也称为APO-1和CD95)及其生理配体FASL调节有害细胞或危险细胞的凋亡,起到抵抗自身免疫和癌症发展的保护作用。不同的细胞类型在“死亡受体” FAS触发其凋亡的机制上有所不同。在I型细胞(例如淋巴细胞)中,通过FAS诱导的caspase-8激活激活“效应半胱天冬酶”足以杀死细胞,而在II型细胞(包括肝细胞和胰腺β细胞)中,caspase通过caspase-8级联扩增介导的促凋亡BCL-2家族成员BID(BH3相互作用域死亡激动剂)的激活至关重要。在这里,我们显示通过基因靶向或用第二个线粒体衍生的胱天蛋白酶激活剂(SMAC,也称为DIABLO;具有低pI的直接IAP结合蛋白)模拟药物治疗,XIAP(X染色体连锁的凋亡蛋白抑制剂)功能丧失在小鼠中,FAS诱导的肝细胞和β细胞独立于BID而不会引起FAS诱导的凋亡。这些结果表明,XIAP是区分I型和II型细胞凋亡信号的关键因素,并建议在患有潜在肝病的癌症患者中谨慎使用IAP抑制剂。

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  • 来源
    《Nature》 |2009年第7258期|1035-1039|共5页
  • 作者单位

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia Department of Medical Biology, Melbourne University, Parkville, Victoria 3050, Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia;

    Department of Medical Biology, Melbourne University, Parkville, Victoria 3050, Australia St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia;

    Institute of Biochemistry, LaTrobe University Bundoora, Victoria 3036 Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia;

    St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia;

    Institute of Molecular Medicine and Cell Research, Centre for Biochemislry and Molecular Ceil Research, Freiburg, D79104, Germany;

    institute of Biochemistry, LaTrobe University Bundoora, Victoria 3036 Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia;

    The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia Institute of Pharmacology, University of Bern, Bern, CH-3010, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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